Dr. Benjamin Houseman is an assistant professor of anesthesia at the University of California - San Francisco whose research develops selective pharmacologic tools to reduce the systemic inflammatory response following trauma. He complements his research interests in cellular and molecular pharmacology with clinical work in anesthesiology at San Francisco General Hospital, the only Level I trauma center in San Francisco. Career goals and development plan Dr. Houseman is interested in developing the skills necessary to conduct focused, mechanistic studies of selective phosphoinosotide-3-kinase (PI3K) inhibitors using in vitro and in vivo models of injury. To achieve this goal, he has assembled a team of accomplished physicians and scientists at UCSF who will mentor his pursuit of the four research aims outlined in this proposal. Dr. Houseman has also identified specific coursework, seminars, and conferences that complement this laboratory research. In the long term, Dr. Houseman wishes to pursue a career in academic medicine that combines patient care with an independently funded translational research program. Research Summary Trauma is the leading cause of death and disability in patients less than 40 years old. While much effort has been paid to the resuscitation and treatment of patients of who survive their initial injury, trauma itself induces a state of profound immunological and endothelial dysfunction characterized by coagulopathy, massive inflammation, and increased endothelial permeability. There is no effective treatment for these processes, as they result from the upregulation of a wide variety of cytokine and chemokine signaling pathways. In both the endothelium and the innate immune system, however, specific isoforms of the PI3K pathway function as a molecular gatekeeper downstream of many of these cytokine and chemokine ligands. This proposal tests the hypothesis that selective inhibition of the gamma and delta isoforms of PI3K (PI3K3 and PI3K4) will reduce endothelial permeability and neutrophil activation following injury. Aim 1 of the proposal develops novel, selective inhibitors of PI3K3 and PI3K4 and evaluates these compounds using in vitro lipid kinase and cellular assays. Aim 2 uses a diverse panel of PI3K inhibitors to understand how different isoforms of the enzyme regulate the activation and permeability of endothelium following severe hypoxia, while Aim 3 examines the effectiveness of a combined inhibitor of PI3K3 and PI3K4 in reducing neutrophil activation after injury. Aim 4 of this proposal tests the hypothesis that a combined inhibitor of PI3K3 and PI3K4 will reduce systemic inflammation in a mouse model of massive trauma-hemorrhage. This specific aim not only examines the effect of the drug but also studies how the timing of drug delivery influences neutrophil biofunction, inflammatory markers, and endothelial permeability. Results from Aims 2, 3, and 4 will be verified using cells or mice deficient in specific isoforms of PI3K. Together, the information obtained from these studies will provide valuable mechanistic insight into the regulation of individual isoforms of PI3K after injury and may provide a novel therapeutic approach to reduce reperfusion injury after trauma. PUBLIC HEALTH RELEVANCE: Profound immunological and endothelial dysfunction after injury represent significant sources of morbidity and mortality. This proposal develops selective inhibitors of the phosphoinositide-3-kinase pathway and utilizes these inhibitors to reduce inflammation and endothelial dysfunction after trauma.